A fungus of the genus Fusarium distributed in association with higher marine plants has proven to be a promising source for the production of sansalvamide, a kind of cytotoxic cyclic depsipeptide.
Sansalvamide A was first reported to be produced by Halodule wrightii, a kind of marine microorganisms [Belofsky G N, Jensen P R, Fenical W. (1999) Sansalvamide: A new cytotoxic cyclic depsipeptide produced by a marine fungus of the genus Fusarium. Tetrahedron Lett. 40, 2913-2916]. It is composed of four hydrophobic amino acid residues (phenylalanine, two leucines, valine) and one hydroxy acid ((S)-2-hydroxy-4-methylpentanoic acid; O-Leu) with five stereogenic centers all having S-stereochemistry. Sansalvamide A was found to have marked anti-proliferative effects on 60 cell lines of the National Cancer Institute, with inhibitory activity against topoisomerase I. Anti-cancer effects of Sansalvamide A may be, at least in part, mediated by this mechanism. Further, the analogues formed by N-methylation or para-bromination of sansalvamide A of FIG. 1 were also found to exhibit remarkable cytotoxicity against human pancreatic cancer cells, suggesting that these cyclic compounds may be highly useful as anti-cancer agents [Ujiki M B, Milam B, Ding X Z, Roginsky A B, Salabat M R, Talamonti M S, Bell R H, Gu W, Silverman R B, Adrian T E. (2006) A novel peptide sansalvamide analogue inhibits pancreatic cancer cell growth through G0/G1 cell-cycle arrest. Biochem. Bioph. Res. Co. 340, 1224-1228].
Recently, N-methylsansalvamide, a sansalvamide analogue with N-methylation, has been produced from different Fusarium species isolated from green algae. It consists of four amino acid residues (phenylalanine, leucine, N-methylleucine and valine) and one hydroxy acid (O-Leu). N-Methylsansalvamide was reported to exhibit in vitro cytotoxicity in the NCI human tumor cell line screen [Cueto M, Jensen P R, Fenical W. (2000) N-Methylsansalvamide, a cytotoxic cyclic depsipeptide from a marine fungus of the genus Fusarium. Phytochemistry. 55, 223-226].
Multidrug resistance (MDR) is arising as one of the major obstacles to successful chemotherapy for human cancer. A variety of biochemical, pharmacological and clinical strategies for overcoming MDR have been designed and suggested [Teodori E, Dei S, Scapecchi S, Gualtieri F. (2002) The medicinal chemistry of multidrug resistance (MDR) reversing drugs. II Farmaco 57, 385-415]. Although there are several mechanisms associated with MDR, the overexpression of P-glycoproteins (P-gp) and multidrug resistance-associated proteins (MRP) is known to be responsible for the development of MDR in cancer cells [Thomas H, Coley H M. (2003) Overcoming multidrug resistance in cancer: an update on the clinical strategy of inhibiting P-glycoprotein. Cancer Control 10, 159-165; Perez-Tomas R. (2006) Multidrug resistance: retrospect and prospects in anti-cancer drug treatment. Curr. Med. Chem. 13, 1859-1876].
Sansalvamide A is a lipophilic, cyclic depsipeptide, which is of protease resistance and membrane permeability, so that it may advantageously take an oral route, compared to other drugs. In addition, forming a cyclic core structure, composed of four amino acids and one hydroxy acid, in which rotation around C—C bonds is restricted, sansalvamide A has a firm conformation which is of excellent compatibility to the body and enjoys a long half life.
Although there have been a number of sansalvamide analogues synthesized to utilize the structural merits and the cytotoxicity against cancer cells of sansalvamide A or N-methylsansalvamide, none of them are concerned with separated, cyclic pentadepsipeptides.